Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 309, Issue 7, Pages L710-L724Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00134.2015
Keywords
lung development; gasotransmitter; hydrogen sulfide; H2S; alveolarization
Categories
Funding
- Max Planck Society
- German Research Foundation [Mo 1789/1]
- Excellence Cluster [147, 306]
- Federal Ministry of Higher Education, Research and the Arts of the State of Hessen LOEWE Program
- German Center for Lung Research (Deutsches Zentrum fur Lungenforschung)
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [25460072, 25220103]
- Grants-in-Aid for Scientific Research [25460072] Funding Source: KAKEN
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The gasotransmitter hydrogen sulfide (H2S) is emerging as a mediator of lung physiology and disease. Recent studies revealed that H2S administration limited perturbations to lung structure in experimental animal models of bronchopulmonary dysplasia (BPD), partially restoring alveolarization, limiting pulmonary hypertension, limiting inflammation, and promoting epithelial repair. No studies have addressed roles for endogenous H2S in lung development. H2S is endogenously generated by cystathionine beta-synthase (Cbs) and cystathionine gamma-lyase (Cth). We demonstrate here that the expression of Cbs and Cth in mouse lungs is dynamically regulated during lung alveolarization and that alveolarization is blunted in Cbs(-/-) and Cth(-/-) mouse pups, where a 50% reduction in the total number of alveoli was observed, without any impact on septal thickness. Laser-capture microdissection and immunofluorescence staining indicated that Cbs and Cth were expressed in the airway epithelium and lung vessels. Loss of Cbs and Cth led to a 100-500% increase in the muscularization of small-and medium-sized lung vessels, which was accompanied by increased vessel wall thickness, and an apparent decrease in lung vascular supply. Ablation of Cbs expression using small interfering RNA or pharmacological inhibition of Cth using propargylglycine in lung endothelial cells limited angiogenic capacity, causing a 30-40% decrease in tube length and a 50% decrease in number of tubes formed. In contrast, exogenous administration of H2S with GYY4137 promoted endothelial tube formation. These data confirm a key role for the H2S-generating enzymes Cbs and Cth in pulmonary vascular development and homeostasis and in lung alveolarization.
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